The disease endometriosis is defined as the growth of endometrial glandular epithelium and stroma at an extrauterine, or "ectopic" site. Ectopic implantation of endometrial tissue entering the peritoneal cavity via retrograde menstruation requires an invasive event and the biomolecules necessary for establishment of endometriosis include the matrix metalloproteinases (MMPs). The MMPs are expressed during estrogen mediated endometrial growth and as a component of menstrual breakdown and subsequent repair processes. The MMPs are not normally expressed during the secretory phase of the menstrual cycle in vivo and are suppressed by progesterone in vitro. Our laboratory has linked MMP expression by human endometrial tissue to establishment of experimental endometriosis. In this model, we find that suppressing the secretion of MMPs or blocking their action with a natural inhibitor prevents formation of endometriotic-like lesions by human tissue injected into the peritoneum of nude mice. The association of steroids mediated MMP expression to the establishment of ectopic lesions in our experimental model appears to link the recognized role of estrogen to promoting the development of endometriosis in women and perhaps explains the protective effects ascribed to progesterone. Although local tissue production of transforming growth factor-Beta (TGF-Beta) acts in concert with progesterone via stromal-epithelial communication to suppress MMPs in the normal endometrium, TGF-Beta can not sustain MMP suppression in the absence of progesterone. We have identified local retinoic acid (RA) synthesis in the endometrium and found that RA may be necessary for normal suppression of MMP expression in concert with progesterone. Alternatively, the local production of interleukin 1 (IL-1) may work in opposition to progesterone to stimulate MMP expression. Clearly, alterations in the local production of key cytokines, a condition that has been documented in endometriosis tissue compared to normal endometrium, may cause aberrant MMP expression. To address these issues experimentally, our specific aims are to 1) to examine the role of progesterone versus progesterone-mediated cytokines relative to aberrant MMP expression in endometriosis tissues, 2) to determine the role that aberrant MMP expression plays in establishment and progression of endometriotic lesions in an experimental model, 3) to determine the interactive roles of RA and TGF-Beta in progesterone-mediated MMP suppression in normal endometrium and endometriosis tissues, and 4) to establish the role of IL-1 in opposing progesterone-mediated MMP suppression in normal endometrium and endometriosis tissues.